This invention relates to isoxazole derivatives useful in the treatment of a variety of conditions mediated by endothelin and to pharmaceutical formulations containing such compounds useful for the treatment of humans and non-human mammals.
Endothelin (ET) is a potent vasoconstrictor synthesized and released by endothelial cells. There are three distinct isoforms of ET: ET-1, ET-2 and ET-3, all being 21-amino acid peptides and herein the term xe2x80x98endothelinxe2x80x99 refers to any or all of the isoforms. Two receptor subtypes, ETA and ETB have been pharmacologically defined (see for example H. Arai et al., Nature, 348, 730, 1990) and further subtypes have recently been reported. Stimulation of ETA promotes vasoconstriction and stimulation of ETB receptors causes either vasodilation or vasoconstriction. The main effects of ET are observed in the cardiovascular system, particularly in the coronary, renal, cerebral and mesenteric circulation, and the effects of endothelin are often long-lasting. Stimulation of ET receptors also mediate further biological responses in cardiovascular and non-cardiovascular tissues such as cell proliferation and matrix formation.
Increased circulating levels of endothelin have been observed in patients who have undergone percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara et al.,Metab. Clin. Exp. 40, 1235, 1991) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al., J.Cardiovasc. Pharm., 22 (Suppl 8), 371, 1993). The same workers have found that an endothelin antagonist, SB-209670, causes a 50% reduction in neointimal formation relative to control animals (S. Douglas et al., Circ. Res, 75, 1994). Antagonists of the endothelin receptor may thus be useful in preventing restenosis post PTCA. The ETA/B receptor antagonist Bosentan reportedly decreased blood pressure in hypertensive patients (H. Krum et al., New Eng. J. Med. (1998) 338, 784-790). Antagonists of ETB receptors such as BQ-788 have been demonstrated to increase peripheral resistance in man (Hypertension (1999) 33, 581-585). Thus ETA-selective receptor antagonists are of benefit in hypertension.
Endothelin-1 is produced in the human prostate gland and endothelin receptors have been identified in this tissue (Y. Saita et al., Eur. J. Pharmacol. (1988) 349, 123-128). Since endothelin is a contractile and proliferative agent, endothelin antagonists are useful in the treatment of benign prostate hypertrophy.
There is widespread localization of endothelin and its receptors in the central nervous system and cerebrovascular system (R. K. Nikolov et al., Drugs of Today, 28(5), 303, 1992) with ET being implicated in cerebral vasospasm, cerebral infarcts, septic shock, myocardial infarction and neuronal death.
Elevated levels of endothelin have also been observed in patients with:
recurrent airway obstruction (Pulm. Pharm. Ther., (1998) 11: 231-235);
asthma (Am. J. Resp. Crit. Care Med., (1995) 151:1034-1039);
acute renal failure (K. Tomita, et al, Med. Philos. (1994) 13(1), 64-66);
chronic renal failure (F. Stockenhuber et al., Clin. Sci. (Lond.), 82, 255, 1992);
ischaemic Heart Disease (M. Yasuda, Am. Heart J., 119, 801, 1990);
stable or unstable angina (J. T. Stewart, Br. Heart J., 66, 7 1991);
pulmonary hypertension (D. J. Stewart et al., Ann. Internal Medicine, 114, 464, 1991);
congestive heart failure (R. J. Rodeheffer et al., Am. J Hypertension, 4, 9A, 1991);
preeclampsia (B. A. Clark et al., Am. J. Obstet. Gynecol., 166, 962, 1992);
diabetes (A. Collier et al., Diabetes Care, 15 (8), 1038, 1992);
Crohn""s disease (S. H. Murch et al., Lancet, 339, 381, 1992); and
atherosclerosis (A. Lerman et al., New Eng. J. Med., 325, 997, 1991).
In every case the disease state associated with the physiologically elevated levels of endothelin is potentially treatable with a substance which decreases the effect of endothelin, such as an endothelin receptor antagonist, or a compound which binds endothelin such that it reduces the effective concentration thereof at the endothelin receptors.
Compounds that antagonize the ETA receptor to a greater extent than the ETB receptor are preferred as ETA receptors are predominantly present in vascular smooth muscles. Blockade of ETB receptor activation may reverse endothelial dependent vasodilation which is beneficial in hypertension. ET may also mediate regeneration of damaged tissue via the ETB receptor, such as proximal tubule cells in the kidney. Thus blockade of ETB receptors, e.g. with a non-selective ET antagonist could inhibit tissue repair. ETB receptors are also involved in the clearance of ET from the systemic circulation. Increased levels of ET are generally considered detrimental. Rises in circulating levels have been observed with non-selective ET antagonists. Treatment with selective ETA receptor antagonists is not likely to induce such rises in circulating levels.
There are a number of publications relating to N-(pyrimidin-4-yl)sulphonamide derivatives having endothelin binding/antagonist activity, for example EP-A-0743307, EP-A-0658548, EP-A-0633259, EP-A-0882719, WO-A-96/20177, EP-A-15 0801062, WO-A-97/09318, EP-A-0852226, EP-A-0768304, WO-A-96/19459, WO-A-98/03488, WO-A-98/57938, WO-A-99/36408, WO-A-01/17976 and EP-A-0713875.
Various N-4-pyrimidinyl sulphonamide derivatives possessing endothelin antagonist activity are described in EP-A-0882719, JP-A-09059160, JP-A-1 0194972 and JP-A-1 0226649.
International Patent Application publication number WO-A-96/19455 discloses phenyl and pyridin-4-yl sulphonamides as endothelin antagonists.
International Patent Application publication number WO-A-97/11942 discloses various (4-arylthioisoxazol-3-yl)sulphonamides, with an aldehyde moiety linked to the 5-position of the isoxazole ring, as selective ETB receptor selective antagonists.
We have unexpectedly found that isoxazoles of formula (I) below have good affinity for endothelin receptors, and are selective for ETA over ETB. 
wherein
R1 is
a) a phenyl group,
b) a 5- or 6-membered heterocyclic group containing one to three heteroatoms each independently selected from the group consisting of N, O and S, said heterocyclic group being optionally fused to a benzo group,
c) CHR6CHR7Ph, or
d) CR6xe2x95x90CR7Ph,
xe2x80x83where groups (a) (b) and (c) are optionally each independently substituted with one to three substituents selected from the group consisting of halo, C1-6 alkyl optionally substituted by OH, halogen, NR4R5, OCOR4, CO2R4, CN, O(C1-6 alkyl optionally substituted by one or more halogens), and CO2R4, where R4 and R5 are each independently H or C1-6 alkyl optionally substituted by one or more halo, and R6 and R7 are each independently H or C1-3 alkyl;
R2 is aryl1 or het1; and
R3 is H, C1-6 alkyl, C(O)R4, CONHaryl1, CONHhet1, aryl1 and het1;
where aryl1 is a phenyl or a naphthyl group, said phenyl and said naphthyl groups being optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, OCF3, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4COR5, COCF3, CH2OH, S(O)pCF3, C(xe2x95x90NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2,
het1 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting N, O and S, said heterocyclic group being optionally fused to a benzo group and optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, CF3O, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(xe2x95x90NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2, with the proviso that when R3 is het1, the het1, group is linked to the adjacent O atom by a carbon atom,
het2 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting of N, O and S,
and p is 0, 1 or 2;
or a pharmaceutically acceptable derivative thereof.
The term xe2x80x9cpharmaceutically acceptable derivativesxe2x80x9d refers to prodrugs of the compounds of Formula (I) as well as the pharmaceutically acceptable salts, hydrates and solvates of the compounds of Formula (I) and prodrugs thereof. For example, pharmaceutically acceptable derivatives include those compounds in which the functional groups explicitly recited above have been derivatized to provide prodrugs which can be converted to the parent compound in vivo. Such prodrugs are discussed in Drugs of Today, Vol. 19, 499-538 (1983) and Annual Reports in Medicinal Chemistry, Vol. 10, Ch. 31 p306-326. The term pharmaceutically acceptable derivatives also includes veterinarily acceptable derivatives and any zwitterionic or tautomeric species that may exist.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
Alkyl, alkenyl and alkynyl groups may be straight chain, branched or cyclic where the number of carbon atoms allows.
Preferably R1 is either
a) a phenyl group, or
b) a 5-7 membered heterocyclic group containing 1-3 heteroatoms each independently selected from the group consisting of O, S and N;
the phenyl and the heterocyclic groups may be optionally substituted by 1-3 substituents each independently selected from the group consisting of halo and C1-6 alkyl optionally substituted by OH or CO2H.
More preferably R1 is a phenyl group optionally substituted by C1-6 alkyl, where the C1-6 alkyl group is optionally substituted by OH or CO2H.
Most preferably R1 is phenyl substituted at the 4 position by t-butyl or 2-hydroxy-1,1-dimethylethyl.
Preferably R2 is either
a) a phenyl group or
b) a 5-7 membered heterocyclic group containing 1-3 heteroatoms each independently selected from the group consisting of O, S and N, where the heterocyclic group is optionally fused to a benzo group, and the phenyl and heterocyclic groups are optionally substituted by 1-3 substituents selected from the group consisting of halogen and C1-6 alkyl optionally substituted by OH or CO2H.
More preferably R2 is benzodioxol or 4-methylphenyl.
Most preferably R2 is a 1,3-benzodiox-5-ol.
Preferably R3 is hydrogen, C1-6 alkyl, C(O)C1-6 alkyl, phenyl, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms each independently selected from the group consisting of O, S and N, where the heterocyclic group is optionally fused to a benzo group, and the phenyl and the heterocyclic groups are optionally substituted by halo, (C1-5 alkyl)OH, (C1-5 alkyl)CO2H, or SOpR4, where p is 0, 1 or 2.
More preferably R3 is hydrogen, C(O)CH3, or a pyrimidine optionally substituted by chloro, bromo, (C1-5 alkyl)OH, (C1-5 alkyl)CO2H, or SOpCH3, where p is 0, 1 or 2.
Most preferably R3 is 4-chloropyrimidinyl
Preferably R4 and R5 are hydrogen or C6 alkyl.
More preferably R4 and R5 are hydrogen or C1-6 alkyl.
Most preferably R4 and R5 are CH3.
Preferably R6 and R7 are hydrogen or CH3.
More preferably R6 and R7 are hydrogen.
Preferred sets of compounds are those described in the Examples and pharmaceutical derivatives thereof.
Most preferred are the compounds:
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl) oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzenesulfonamide;
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl) oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzenesulfonamide; or
N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-isoxazolyl)-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide.
The compounds of the present invention may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic substances may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediates may be resolved and used to prepare chiral compounds of formulae (IA) and (IB).
The compounds of the invention are useful because they blockade ET receptors and are thus useful in the treatment or prevention of any diseases for which such a blockade is beneficial. More particularly, they are useful in the treatment and prevention of restenosis, acute/chronic renal failure, hypertension including pulmonary and systemic hypertension; benign prostatic hypertrophy, male erectile dysfunction, prostate cancer, metastatic bone cancer, congestive heart failure, stroke, subarachnoid haemorrhage, angina, atherosclerosis, cerebral and cardiac ischaemia, prevention of ischaemia/reperfusion injury (e.g. allografts), cyclosporin induced nephrotoxicity, glaucoma, radiocontrast nephropathy, diabetic neuropathy, allergy, restoration of organ perfusion in haemorrhagic shock, lipoprotein lipase related disorders, chronic obstructive pulmonary disease and hyaline membrane disease in newborn. The treatment of congestive heart failure, restenosis, renal failure and systemic and pulmonary hypertension are of particular interest. The compounds of the present invention may be administered alone or as part of a combination therapy.